Compositions using optically pure R(+) ondansetron

ABSTRACT

Methods and compositions are disclosed utilizing the optically pure R(+) isomer of ondansetron. This compound is a potent drug for the treatment of nausea and vomiting associated with chemotherapy and radiation therapy, while avoiding the concomitant liability of adverse effects associated with the racemic mixture of ondansetron. The R(+) isomer of ondansetron is also useful for the treatment of behavioral disorders such as mood anxiety and schizophrenia, and such other conditions as may be related to R(+) ondansetron&#39;s activity as a competitive antagonist of serotonin receptor subtype 5-HT3 such as disorders of gastrointestinal motility, depression, migraine, and as an aid for alcohol withdrawal, nicotine withdrawal, and drug (benzodiazepine et al.) withdrawal, without the concomitant liability of adverse effects associated with the racemic mixture of ondansetron. Furthermore, the R(+) isomer of ondansetron is also useful for the treatment of cognitive disorders such as dementia or age-associated memory impairment, while avoiding the concomitant liability of adverse effects associated with the racemic mixture of ondansetron.

This is a continuation of application Ser. No. 08/164,734, filed Dec. 7,1993, now U.S. Pat. No. 5,470,868, which is a continuation ofapplication Ser. No. 07/750,387, filed Aug. 27, 1991, now abandoned,which is a continuation-in-part of application Ser. No. 07/721,868,filed Jun. 26, 1991, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel compositions of matter containingoptically pure R(+) ondansetron. These novel compositions have potentantiemetic activity and are useful in ameliorating the nausea andvomiting otherwise induced by cancer chemotherapeutic agents and higherdose radiotherapeutic treatment procedures while avoiding adverseeffects including but not limited to headache, constipation andincreases in transaminase levels, which are associated with theadministration of the racemic mixture of ondansetron. Additionally,these novel compositions of matter containing optically pure R(+)ondansetron are useful in treating behavioral disorders such as moodanxiety and schizophrenia, and such other conditions as may relate toR(+) ondansetron's activity as a competitive antagonist of serotoninreceptor subtype 5-HT₃, including but not limited to disorders ofgastrointestinal motility, depression, migraine, alcohol, nicotine ordrug (benzodiazepine et al.) withdrawal, while avoiding adverse effectsassociated with the administration of the racemic mixture ofondansetron. Furthermore, these novel compositions of matter containingoptically pure R(+) ondansetron are useful in treating cognitivedisorders such as dementia and age-associated memory impairment, whileavoiding the adverse effects associated with the administration of theracemic mixture of ondansetron. Also disclosed are methods for treatingthe above described conditions in a human while avoiding the adverseeffects that are associated with the racemic mixture of ondansetron, byadministering the R(+) isomer of ondansetron to said human.

The active compound of this composition, and method is an optical isomerof the compound, ondansetron which is described in U.S. Pat. No.4,695,578. Chemically, the active compound is the R(+) isomer of1,2,3,9-tetrahydro-9-methyl-3-(2-methyl-1H-imidazol-1-yl)methyl!-4H-carbazol-4-one. This isomer willhereinafter be referred to as R(+) ondansetron.

1.1. Steric Relationships and Drug Action

Many organic compounds exist in optically active forms, i.e., they havethe ability to rotate the plane of plane-polarized light. In describingan optically active compound, the prefixes D and L or R and S are usedto denote the absolute configuration of the molecule about its chiralcenter(s). The prefixes (+) and (-) or d and 1 are employed to designatethe sign of rotation of plane-polarized light by the compound, with (-)or 1 meaning that the compound is levorotatory. A compound prefixed with(+) or d is dextrorotatory. For a given chemical structure, thesecompounds, called stereoisomers, are identical except that they aremirror images of one another. A specific stereoisomer may also bereferred to as an enantiomer, and a mixture of such isomers is oftencalled an enantiomeric or racemic mixture.

Stereochemical purity is of importance in the field of pharmaceuticals,where 12 of the 20 most prescribed drugs exhibit chirality. A case inpoint is provided by the L-form of the β-adrenergic blocking agent,propranolol, which is known to be 100 times more potent than theD-enantiomer.

Furthermore, optical purity is important since certain isomers mayactually be deleterious rather than simply inert. For example, it hasbeen suggested that the D-enantiomer of thalidomide was a safe andeffective sedative When prescribed for the control of morning sicknessduring pregnancy, and that the corresponding L-enantiomer, a potentteratogen.

Ondansetron, which is the subject of the present invention, is availablecommercially only as the 1:1 racemic mixture; i.e., it is a mixture ofoptical isomers, called enantiomers. The racemic mixture of ondansetronis a dihydrate, that is administered as a hydrochloride salt. Theenantiomers of ondansetron are disclosed in Butler et al., Br. J.Pharmacol., 94, pg. 397-412 (1988). This reference states that the R andS isomers of ondansetron were approximately equipotent as 5-HTantagonists on rat vagus nerve. Furthermore, the reference alleges thatthe racemic mixture caused concentration-dependent parallel rightwarddisplacement of the 2-methyl -5-HT concentration response curve whenexposed to the longitudinal smooth muscle of the guinea-pig ileum, andthat the R isomer was more potent than the S isomer when administeredcompetitively against 2-methyl-5-HT.

The racemic mixture of ondansetron is an antagonist of the5-hydroxytryptamine (5-HT₃ or serotonin) receptor. The role ofserotonin, and thus the pharmacology of ondansetron has been broadlyimplicated in a variety of conditions for many years (see, Phillis, J.W., The Pharmacology of Synapses, Pergamon Press, Monograph 43, 1970;Frazer,. A. et al. Annual Rev. of Pharmacology and Therapeutics 30,307-348, 1990). Thus, research has focused on locating the productionand storage sites of serotonin as well as the location of serotoninreceptors in the human body in order to determine the connection betweenthese sites and various disease states or conditions.

In this regard, it was discovered that a major site of production andstorage of serotonin is the enterochromaffin cell of thegastrointestinal mucosa. It was also discovered that serotonin has apowerful stimulating action on intestinal motility by stimulatingintestinal smooth muscle, speeding intestinal transit, and decreasingabsorption time, as in diarrhea. This stimulating action is alsoassociated with nausea and vomiting.

Thus, researchers studied diseases and treatment of diseases where theabove described effects were manifested. One such treatment is chemo-and radio-therapy of cancer using chemotherapeutic and high doseradiotherapeutic agents. Chemo-and radio-therapy may induce nausea andvomiting by the release of serotonin from damaged enterochromaffin cellsin the gastrointestinal tract. Release of the neurotransmitterserotonin, stimulates both afferent vagal nerve fibers (thus initiatingthe vomiting reflex) and serotonin receptors in the chemoreceptortrigger zone of the area postrema region of the brain.

One of the first agents used to prevent the nausea and vomitingassociated with emetogenic cancer chemotherapy was metoclopramide. Thiscompound is an antagonist of central and peripheral dopamine receptors,and at high doses it also antagonizes serotonin receptors. Because ithad this combined effect, researchers began to search for a morespecific and safer serotonin 5-HT₃ antagonist to use to treat nausea andvomiting associated with chemo-and radio-therapy of cancer. This led tothe development of ondansetron.

Ondansetron is a competitive antagonist at serotonin 5-HT₃ receptorsubtypes in both the gastrointestinal tract and the brain, where itblocks both sites of serotonin-induced emesis. With respect to itsanti-emetic potential, ondansetron appears to offer a dual mode ofaction through antagonism of serotonin at peripheral vagal nerveafferents, and antagonism of serotonin within the central nervoussystem, at or near the chemoreceptor trigger zone.

Consequently, ondansetron may produce a significant reduction, or acomplete inhibition of nausea and vomiting in the majority of patientssubsequently treated with cancer chemotherapeutics of moderate or highemetic potential. Similarly, the compound prevented radiation-inducednausea and emesis. Further, ondansetron appears to have an effect ongastrointestinal motility slowing the transit of material throughportions of the tract. This decrease in motility may be beneficial inthose patients undergoing the chemotherapy for cancer where diarrhea canprovide an additional debilitating burden.

Ondansetron's use as an antiemetic by either the intravenous or oralroutes is disclosed in U.S. Pat. Nos. 4,753,789 and 4,929,632.Furthermore, various researchers have tested the use of the racemicmixture of ondansetron to prevent nausea and vomiting caused byanticancer chemotherapy. See, Green et al., Cancer Chemother.Pharmacol., 24:137-139 (1989); Cubeddu et al., New Enql. J. Med., Vol.322; No. 12, pg. 810-815 (1990); De Mulder et al., Ann. Int. Med., Vol.113: No. 11, pg. 834-840 (1990); Marty, Eur. J. Cancer Clin. Oncol.,Vol. 25, Suppl. 1, pg. 541-545 (1989); Khojasteh et al., Cancer, Vol.66, No. 6, pg. 1101-1105 (1990); Schmoll, Eur. J. Cancer Clin. Oncol.,Vol. 25, Suppl. 1, pg. 535-539 (1989); Grunberger et al., J. Clin.Oncol., Vol. 7, No. 8, pg. 1137-1141 (1989); Kris et al., J. Clin.Oncol., Vol. 6, no. 4 pg. 659-662 (1988).

Thus, in the context of adjunctive therapy for cancer treatment,ondansetron appears to be an effective antiemetic, although itsdose-response relationships remain to be clarified. The drug offers amoderate potency, a half-life of some three hours, and the potential forprophylactic/therapeutic activity. Dosing 1-2 hours prior to cancertherapy or at the initiation of therapy can be accomplished bycontinuous infusion, or repeated Oral or intravenous administrations.(see Smith, R. N., Safety of Ondansetron, European. J. of Cancer andClinical Oncology, 25 Suppl.1 547-50, 1989; and Smyth, J. F. ibid.,555-57, 1989).

As stated previously, stimulation of serotonin receptors has beenpostulated to be involved in a variety of disease states and conditions.Thus, it has been proposed that antagonizing serotonin receptors willassist in treating these conditions.

It has been proposed that the racemic mixture of ondansetron is usefulin the treatment of anxiety disorders. Anxiety disorder has its etiologyin both psychologic and physiologic factors, and it has been suggestedthat a genetic influence exists. Emotional stress can precipitateanxiety neurosis which represents the individual's fear of losingcontrol of such emotional drives as aggression or dependency needs, andlosing control of one's resulting actions. Physiologically, anxiety isassociated with autonomic nervous system discharge, and relatedneurohumoral processes. In acute anxiety attacks, lasting from a fewminutes to an hour, the individual experiences a subjective sense ofterror, for no evident reason, and perhaps a haunting dread ofcatastrophe. Chronic anxiety displays less intense symptoms of longerduration, characterized by uneasiness, nervousness, nagging uncertaintyabout future events, headache, fatigue and subacute autonomic symptoms.The use of the racemic mixture of ondansetron to treat anxiety disordersis disclosed in U.S. Pat. No. 4,695,578.

It has also been proposed that the racemic mixture of ondansetron isuseful to treat psychotic disorders such as schizophrenia. (See U.S.Pat. No. 4,695,578). Schizophrenic disorders are complex mentaldisorders which tend toward chronicity, and which impair functioning,and are characterized by psychotic symptoms of disturbed thinking,feeling and general behavior. Clear, goal directed thought becomesdifficult, while blunting and inappropriate affect become the mostcharacteristic emotional changes. Auditory hallucinations can be common,and delusions of persecution are frequent, as are threats of violence,and minor aggressive outbursts. Disturbances of movement can range fromsignificant over-activity and excitement to retardation and stupor.Treatment has often included tranquilizer and other antipsychotic drugs,administered orally or by long acting depot injections (to offsetproblems of patient compliance).

The racemic mixture of ondansetron has also been proposed to be usefulin the treatment of depression (see U.S. Pat. No. 4,835,173).Depression, an affective disorder, is characterized by changes in mood.,as a primary clinical feature. The most common of the significant mentalillnesses, depression must be distinguished clinically from periods ofnormal grief, sadness, and disappointment, and the related dysphoria ordemoralization frequently associated with medical illness. Depression ischaracterized by feelings of intense sadness, and despair, mentalslowing and loss of concentration, pessimistic worry, agitation, andself-deprecation. Physical changes can also occur, including insomnia,anorexia, and weight loss, decreased energy and libido, and thedisruption of circadian rhythms. Often the condition responds well totricyclic or related antidepressant drugs, monoamine oxidase inhibitors,or in resistant cases or severe disease, to electro-convulsive shocktreatment. Nevertheless, the treatment of depression would benefit fromnew therapy.

It has also been proposed that the racemic mixture of ondansetron isuseful to treat migraine (see U.S. Pat. No. 4,695,578). Migraine is ofunknown cause, although evidence suggests a functional disturbance ofthe cranial circulation. The condition is a paroxysmal disorder,characterized by recurrent attacks of headache, which can be associatedwith visual and gastrointestinal disturbances. Migraine headaches may bepreceded by a short period of depression, irritability, restlessness oranorexia.

U.S. Pat. No. 4,847,281 discloses the use of the racemic mixture ofondansetron to treat substance abuse. Disorders of substance use orabuse often involve both psychologic and physical dependence,accompanied by the development of tolerance (the need to increase thedose progressively so as to produce the effect originally achieved bysmaller amounts), and manifested by a withdrawal or abstinence syndrome.

Alcohol withdrawal syndrome represents a continuum of symptoms includingtremor, weakness, sweating and gastrointestinal symptoms usuallybeginning some hours after cessation of intake. Drugs which alter theserotonin system can modulate the alcohol consumption in humans. Somemutual, but incomplete cross-tolerance exists between alcohol and otherdrugs including the benzodiazepines, the sedative-hypnotic, and theanxiolytic muscle relaxant group. While benzodiazepine withdrawalsymptoms are often considered moderate, in withdrawal, often anxietyreturns, with dysphoria irritability, sweating, headache and sleepabnormalities. Nicotine withdrawal syndrome following cessation oftobacco use, varies significantly among subjects in intensity, andspecific signs and symptoms. Apart from the craving for tobaccoproducts, which begins within 24 hours of cessation and then subsidesover a period of some days, other symptoms include, but are not limitedto, irritability, anxiety, increased appetite and the gastrointestinalsymptoms, and inability to concentrate.

In addition, the racemic mixture of ondansetron could be useful in thetreatment of cognitive disorders. Cognitive disorders include but arenot limited to dementia and age-associated memory impairment.

Dementia can occur at any age. It is a structurally caused permanent orprogressive decline in several dimensions of intellectual function thatinterferes substantially with individual normal social or economicactivity.

One particular type of dementia is Alzheimers-type dementia.Alzheimers-type dementia is thought to be due to a degenerative process,with a large loss of cells from the cerebral cortex and other brainareas. Acetylcholine-transmitting neurons and their target nerve cellsare particularly affected. The brain shows marked atrophy with widesulci and dilated ventricles. Senile plaques and neurofibrillary tanglesare present. Memory loss is the most prominent early symptom.Disturbances of arousal do not occur early in the course. Alzheimer'spresenile and senile onset dementias are similar in both clinical andpathologic features, with the former commonly beginning in the 5th and6th decades and the latter in the 7th and 8th decades. The dementiausually progresses steadily, becoming well advanced in 2 to 3 years.Some cases of dementia occurring in the presenile period are hard toclassify and are sometimes labelled idiopathic or simple preseniledementia.

The signs and symptoms of dementia, in particular Alzheimers-typedementia, include depression, paranoia, anxiety or any of several otherpsychologic symptoms. The most common clinical picture is slowdisintegration of personality and intellect due to impaired insight andjudgment and loss of affect. Memory impairment increases, beginning withproblems recalling recent events or finding names. The impairment variesgreatly from time to time and often from moment to moment. Dementiagenerally is an insidious, slowly progressive, untreatable condition.However, the rate of progression varies widely and depends on the cause.

Another type of cognitive disorder is age-associated memory impairment(AAMI). AAMI is used to describe healthy non-demented people who haveexperienced memory loss over the course of the person's life. Mostcommonly it is used to describe adults over the age of 50 who haveexperienced memory loss over the course of adult life. It has beenestimated that between 25% and 150% of people over the age of 65 havethis disorder.

While the racemic mixture of ondansetron offers efficacy in treating avariety of diseased states and conditions, its use is associated withadverse effects (principally headache and constipation) which increasewith the dose of the racemic mixture of ondansetron administered.

Thus it would be particularly desirable to find a compound with theadvantages of ondansetron which would not have the aforementioneddisadvantages.

SUMMARY OF THE INVENTION

It has now been discovered that the optically pure R(+) isomer ofondansetron is an effective anti-emetic agent, useful as an adjunctivetherapy in Cancer treatment to ameliorate nausea and vomiting induced bychemo- or radio-therapeutics, while decreasing the usual adverse effectsincluding, but not limited to, headache, constipation and increases intransaminase levels which are associated with the racemic mixture ofondansetron. It has also been discovered that the optically pure R(+)isomer of ondansetron is a useful agent to treat such behavioraldisorders as mood anxiety and schizophrenia, and such other conditionsas may relate to the composition's activity as a competitive antagonistat. serotonin receptor subtype 5-HT₃, such as disorders ofgastrointestinal motility, depression, migraine, and as a therapeuticaid in alcohol, nicotine, and benzodiazepine withdrawal, whiledecreasing the usual adverse effects associated with the racemic mixtureof ondansetron.

Furthermore, it has also now been discovered that the optically-pureR(+) isomer of ondansetron is useful in treating cognitive disorderssuch as dementia and age-associated memory impairment, while decreasingthe adverse effects associated with the racemic mixture of ondansetron.

The present invention also includes novel compositions of matter,containing optically pure R(+) ondansetron which are useful andeffective as antiemetic adjunctive therapy in cancer treatment bychemo-or radio-therapeutics, and as agents for the aforementioneddisorders. These novel compositions also avoid, or reduce the abovedescribed adverse effects associated with the administration of theracemic mixture of ondansetron. Thus, with the R(+) isomer ofondansetron, clearer dose definitions of efficacy visa vis adverseeffects, may be achieved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention encompasses a method of eliciting an antiemeticeffect while avoiding the concomitant liability of adverse effects whichcomprises administering to a human in need of such antiemetic therapy anamount sufficient to alleviate nausea and vomiting, but insufficient tocause said adverse effects, of R(+) ondansetron, or a pharmaceuticallyacceptable salt thereof, substantially free of its S(-) stereoisomer.

The present invention also encompasses an antiemetic composition for thetreatment of a human in need of antiemetic therapy, which comprises anamount sufficient to alleviate nausea and vomiting but insufficient tocause adverse effects, of R(+) ondansetron, or a pharmaceuticallyacceptable salt thereof, substantially free of its S(-) stereoisomer.

The present invention further encompasses a method of treatingbehavioral disorders such as mood anxiety or schizophrenia in a humanwhile avoiding the concomitant liability of adverse effects, whichcomprises administering to said human in need of such therapy, an amountsufficient to alleviate said condition, but insufficient to cause saidadverse effects, of R(+) ondansetron, or a pharmaceutically acceptablesalt thereof, substantially free of its S(-) stereoisomer.

In addition, the present invention encompasses a composition for thetreatment of a human with behavior disorders such as mood anxiety orschizophrenia, which comprises an amount sufficient to alleviatebehavioral disorders such as mood anxiety or schizophrenia, butinsufficient to cause adverse effects, of R(+) ondansetron, or apharmaceutically acceptable salt thereof, substantially free of its S(-)stereoisomer.

Also included in the present invention is a method of treating acondition caused by disturbance of neuronal 5-HT function while avoidingthe concomitant liability of adverse effects, which comprisesadministering to a human in need of such therapy an amount sufficient toalleviate said condition but insufficient to cause said adverse effects,of R(+) ondansetron, or a pharmaceutically acceptable salt thereof,substantially free of its S(-) stereoisomer. Conditions caused by adisturbance of neuronal 5-HT function include but are not limited to,disorders of gastrointestinal motility, depression, migraine, andalcohol, nicotine, or drug (benzodiazepine et al.) withdrawal.

A further aspect of the present invention is a composition for treatinga condition caused by disturbance of neuronal 5-HT function, whichcomprises an amount sufficient to alleviate said condition butinsufficient to cause adverse effects, of R(+) ondansetron, or apharmaceutically acceptable salt thereof, substantially free of its S(-)stereoisomer.

Furthermore, the present invention includes a method of treatingcognitive disorders such as dementia or age-associated memoryimpairment, while avoiding the concomitant liability of adverse effects,which comprises administering to a human in need of such therapy anamount sufficient to alleviate said cognitive disorder but insufficientto cause said adverse effects, of R(+) ondansetron, or apharmaceutically acceptable salt thereof, substantially free of its S(-)stereoisomer.

A further aspect of the present invention is a composition for treatingcognitive disorders such as dementia or age-associated memoryimpairment, which comprises an amount sufficient to alleviate saidcondition, but insufficient to cause adverse effects, of R(+)ondansetron, or a pharmaceutically acceptable salt thereof,substantially free of its S(-) stereoisomer.

The available racemic mixture of ondansetron (i.e. a 1:1 racemic mixtureof stereoisomers) causes antiemetic activity, and provides therapy and areduction of symptoms in a variety of conditions and disorders; howeverthis racemic mixture, while offering the expectation of efficacy, causesadverse effects. Utilizing the R(+) isomer of ondansetron alone resultsin dose related definitions of efficacy, diminished adverse effects, andaccordingly, an improved therapeutic index. It is therefore, moredesirable to use the R(+) isomer of ondansetron.

The term adverse effects, includes, but is not limited to headache,constipation, fatigue, sedation, lethargy, drowsiness, dry mouth,diarrhea and transient increases in transaminase levels. Increases inthe serum activity of certain hepatocellular enzymes is also includedwithin the term "adverse effects".

The term "substantially free of its S(-) stereoisomer" as used hereinmeans that the composition contains a greater proportion of the R(+)isomer of ondansetron in relation to the S(-) isomer of ondansetron. Inone embodiment the term "substantially free of its S(-) stereoisomer" asused herein means that the composition contains at least 90% by weightof R(+) ondansetron, and 10% by weight or less of S(-) ondansetron. Inthe most preferred embodiment the term "substantially free of the S(-)stereoisomer" means that the composition contains at least 99% by weightR(+) ondansetron, and 1% or less of S(-) ondansetron.

The term, "eliciting an antiemetic effect" as used herein meansproviding relief from the symptoms of nausea and vomiting inducedspontaneously or substantially free of its associated with emetogeniccancer chemotherapy or irradiation therapy.

The term, "behavioral disorders such as mood anxiety, and schizophrenia"as used herein means relief from the symptoms which include, but are notlimited to, a subjective sense of terror, a dread of catastrophe,uneasiness, nervousness uncertainty, headache, fatigue, disturbedthinking, inappropriate affect, auditory hallucinations, aggressiveoutbursts and the like.

The term, "a condition caused by disturbance of neuronal 5-HT function"includes but is not limited to disorders of gastrointestinal motility,depression, migraine and alcohol, nicotine or drug (benzodiazepine etal.) withdrawal. This includes relief from the symptoms which include,but are not limited to, diarrhea and related symptoms, as decreasedabsorption time, etc., intense sadness, despair, mental slowing, lossconcentration, worry, agitation, headache, irritability, restlessness,anorexia, sweating, sleep abnormalities, and the like.

The term "treating cognitive disorders" as used herein means providingrelief from the symptoms of cognitive disorders including but notlimited to memory loss, disintegration of personality and intellect,depression, paranoia, anxiety and other psychologic symptoms.

The preparation of the mixture of enantiomers, (e.g., racemic mixture)of ondansetron is disclosed in U.S. Pat. No. 4,695,578. The R(+) isomerof ondansetron, may be obtained by resolution of the mixture ofenantiomers of ondansetron using conventional means such as an opticallyactive resolving acid; see, for example, "Stereochemistry of CarbonCompounds", by E. L. Eliel (McGraw Hill 1962) and Lochmuller C. H. etal., J. Chromatogr., 1975, Vol. 113, No. 3, Pg. 283-302.

The magnitude of a prophylactic or therapeutic dose of R(+) ondansetronin the acute or chronic management of disease will vary with theseverity of the condition to be treated, and the route ofadministration. The dose, and perhaps dose frequency, will also varyaccording to the age, body weight, and response of the individualpatient. In general, the total, daily dose ranges, for the conditionsdescribed herein, from about 0.01 mg to about 35 mg administered individed doses orally, or by a slow intravenous injection or infusion. Incases of moderate to highly emetogenic chemotherapy, it may be expectedthat, an initial loading dose of between about 2 mg to about 10 mg givenby slow intravenous injection or infusion over 15-3minutes, immediatelybefore the emetogenic chemotherapy, and followed by about 2 mg to about8 mg given orally every eight hours for periods up to four to five dayswill elicit therapy and provide for a reduction of symptoms. In cases ofradiotherapy, and as an oral therapeutic for the other conditionsdescribed herein, generally doses of between about 2 mg to about 8 mgorally every eight hours, should provide benefit to adult patients. Inthe case of using R(+) ondansetron to treat cognitive disorders such asdementia and age-associated memory-impairment, the total daily dosageranges may be from about 0.001 mg to about 35 mg in divided doses orallyor by a slow intravenous injection or infusion. Children generally willbenefit from doses that are generally some 25-50 percent those of theadult for a given condition, while geriatric patients generally tolerateadult doses. It may be necessary to use dosages outside these ranges insome conditions.

The term, "an amount sufficient to alleviate the nausea and vomiting butinsufficient to cause said adverse effects" is encompassed by the abovedescribed dosage amounts and dose frequency schedule. In addition, theterm "an amount sufficient to alleviate said condition but insufficientto cause said adverse effects" wherein said conditions include but arenot limited to behavioral disorders such as mood anxiety andschizophrenia as well as disturbances of neuronal 5-HT functionincluding, but not limited to, disorders of gastrointestinal motility,depression, migraine and alcohol, nicotine or drug (benzodiazepine etal.) withdrawal are also encompassed by the above described amounts. Theterm "an amount sufficient to alleviate said condition but insufficientto cause said adverse effects" wherein said condition includes cognitivedisorders such as dementia and age-associated memory impairment, is alsoencompassed by the above-described amounts.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of R(+) ondansetron. For example, oral,rectal, parenteral, transdermal, subcutaneous, intramuscular, and thelike may be employed. Dosage forms include tablets, troches,dispersions, suspensions, solutions, capsules, patches, and the like.

The pharmaceutical compositions of the present invention comprise R(+)ondansetron as active ingredient, or a pharmaceutically acceptable saltthereof, and may also contain a pharmaceutically acceptable carrier, andoptionally, other therapeutic ingredients. The term "pharmaceuticallyacceptable salts" refers to salts prepared from pharmaceuticallyacceptable non-toxic acids including inorganic acids and organic acids.

Since the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids includinginorganic and organic acids. Such acids include acetic,benzene-sulfonic, benzoic camphorsulfonic, citric, ethenesulfonic,fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic,lactic, maleic, maleic, mandelic, methanesulfonic, mucic, nitric,pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid,p-toluenesulfonic, and the like. Particularly preferred are hydrobromic,hydrochloric, phosphoric and sulfuric acids.

The compositions include compositions suitable for oral, rectal or othermucosal routes, transdermal, parenteral (including-subcutaneous,intramuscular, and intravenous), although the most suitable route in anygiven case will depend on the nature and severity of the condition beingtreated. The most preferred routes of the present invention include bothintravenous injections, and infusions and the oral route. They may beconveniently presented in unit dosage form, and prepared by any of themethods well known in the art of pharmacy.

In the case where an oral composition is employed, a suitable dosagerange for use is, e.g., from about 5 mg to about 35 mg total daily dose,administered as equally divided doses, three times a day. Preferably, adose range of between about 10 mg to about 30 mg per day, administeredas equally divided doses, three times a day, and most preferably frombetween about 12 mg to about 24 mg per day, administered as equallydivided doses, three times a day. Patients may be upwardly titratedwithin this dose range to enable the satisfactory control of symptoms.In the case where an oral composition is employed to treat cognitivedisorders such as dementia and age-associated memory impairment, asuitable dosage range for use is from about 0.001 mg to about 35 mgtotal daily dose administered as equally divided doses from one to threetimes a day. Preferably a dose range of between about 0.001 mg to about20 mg per day administered as equally divided doses one to three times aday and most preferably from between 0.001 mg to about 10 mg per dayadministered as equally divided doses, one to three times a day.

In the case where an intravenous injection or infusion composition isemployed, a suitable dosage range for use is, e.g. from about 0.01 mg toabout 32 mg total daily dose, presented as a loading slow intravenousinjection of about 2 mg to about 8 mg over 15-30 minutes, followed by anintravenous infusion of about 0.5 mg to about 1.0 mg/hour for up to 24hours. These regimens may be followed by oral doses of between about 1.5mg to about 8.0 mg every eight hours for periods up to five days.

In practical use, R(+) ondansetron can be combined as the activeingredient in intimate admixture with a pharmaceutical carrier accordingto conventional pharmaceutical compounding techniques. The carrier maytake a wide variety of forms depending on the form of preparationdesired for administration, e.g. oral or parenteral (includingintravenous injections or infusions). In preparing the compositions fororal dosage form, any of the usual pharmaceutical media may be employed,e.g., water, glycols, oils, alcohols, flavoring agents, preservatives,coloring agents, and the like in the case of oral liquid preparations,e.g., suspensions, solutions, and elixirs; or aerosols; or carriers suchas starches, sugars, micro-crystalline cellulose, diluents, granulatingagents, lubricants, binders, disintegrating agents, and the like in thecase of oral solid preparations e.g., powders, capsules, and tablets,with the solid oral preparations being preferred over the liquidpreparations. The most preferred solid oral preparation is tablets.

Because of their ease of administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are employed. If desired, tablets may be coatedby standard aqueous or nonaqueous techniques.

In addition to the common dosage forms set out above the compounds ofthe present invention may also be administered by controlled releasemeans and/or delivery devices such as those described in U.S. Pat. Nos.:3,845,770; 3,916,899; 3,536,809; 3,598,123; and 4,008,719, thedisclosures of which are hereby incorporated by reference.

Another preferred route of administration, particularly to avoidproblems associated with emesis, is transdermal delivery, for example,via an abdominal skin patch.

Pharmaceutical compositions of the present invention suitable for oraladministration may be presented as discrete units such as capsules,cachets, or tablets, or aerosol sprays, each containing a predeterminedamount of the active ingredient, as a powder or granules, or as asolution or a suspension in an aqueous liquid, a non-aqueous liquid, anoil-in-water emulsion, or a water-in-oil liquid emulsion. Suchcompositions may be prepared by any of the methods of pharmacy, but allmethods include the step of bringing into association, the activeingredient with the carrier which constitutes one or more necessaryingredients. In general, the compositions are prepared by uniformly andintimately admixing the active ingredient with liquid carriers or finelydivided solid carriers or both, and then, if necessary, shaping theproduct into the desired presentation.

For example, a tablet may be prepared by compression or molding,optionally with one or more accessory ingredients. Compressed tabletsmay be prepared by compressing in a suitable machine, the activeingredient in a free-flowing form such as powder or granules, optionallymixed with a binder, lubricant, inert diluent, surface active ordispersing agent. Molded tablets may be made by molding in a suitablemachine, a mixture of the powdered compound, moistened with an inertliquid diluent. Desirably, each tablet contains from about 2.0 mg toabout 8.0 mg of the active ingredient, and each cachet or capsulecontains from about 2.0 mg to about 8.0 mg. of the active ingredient.Most preferably, the tablet, cachet or capsule contains either one ofthree dosages: 2.0 mg, 4.0 mg and 8.0 mg (as scored tablets, thepreferable dose form) of active ingredient. Furthermore, each tablet orcapsule can contain from about 0.001 mg to about 10.0 mg of the activeingredient. However, the amount of active ingredient found in thecomposition may vary depending on the amount of active ingredient to beadministered to the patient.

The invention is further defined by reference to the following examplesdescribing in detail, the preparation of the compound, and thecompositions of the present invention. It will be apparent to thoseskilled in the art, that many modifications, both to materials andmethods, may be practiced without departing from the purpose andinterest of this invention.

All temperatures are in degrees Celsius.

EXAMPLES Example 1

A pharmacological study to determine the relative potency andspecificity of optically pure R(+) ondansetron and racemic ondansetronas competitive antagonists at serotonin receptor subtype 5-HT₃ presentin gastrointestinal, brain, and other tissues.

The optically pure and racemic compounds may be evaluated as a functionof their molar concentration, for their relative abilities to inhibitthe binding of ³ H-5-HT in such selected preparations as nerves ofguinea pig ileum and preparations of brain tissue from several speciesincluding rats and humans. The availability of ³ H-5-HT as a radioligandwith relatively high specific activity, the development of otherselective 5-HT₃ antagonists, and the additional agonist,2-methyl-5-hydroxy-tryptamine (2-methyl-5-HT) provide the pharmacologictools for the characterization of the 5-HT₃ receptor, and the evaluationof R(+), and racemic ondansetron. (see Frazer, A., et al., Annu. Rev.Pharmacol. Toxicol. 30., 307-348, 1990). It has been suggested,(Bradley, P. B et al., Neuropharmacology 25, 563-576, 1986) as part ofthe evolving characterization of serotonin receptor subtypes, thatresponses mediated by 5-HT₃ receptors: be reduced by selectiveantagonists, not be inhibited by selective antagonists of other subtypesof serotonin receptors, and be mimicked by 2-methyl 5-HT atconcentrations comparable to that of serotonin.

Accordingly, the comparative ability of R(+) and racemic ondansetron, toinhibit the binding of ³ H-5-HT and the agonist, ³ H-2-methyl 5-HT, notto be inhibited as a radioligand for 5-HT₃ receptors by selectiveantagonists of other subtypes and to be inhibited from selective bindingas a function of concentration, by other 5-HT₃ selective antagonists ofpossibly greater potency including zacopride, ICS 205-930, andgranisetron, will serve a characterization of potency and specificity at5-HT₃ receptors.

Example

    ______________________________________                                        ORAL FORMULATION                                                              Tablet:                                                                                       Quantity per Tablet                                                           in mg                                                         Formula           A         B      C                                          ______________________________________                                        Active Ingredient 2.0       4.0    8.0                                        R(+) ondansetron                                                              Lactose BP        151.5     149.5  145.5                                      Starch BP         30.0      30.0   30.0                                       Pregelatinized Maize Starch BP                                                                  15.0      15.0   15.0                                       Magnesium Stearate BP                                                                           1.5       1.5    1.5                                        Compression Weight                                                                              200.0     200.0  200.0                                      ______________________________________                                    

The active ingredient, is sieved through a suitable sieve and blendedwith lactose, starch, and pregeatinised maize starch. Suitable volumesof purified water are added and the powders are granulated. Afterdrying, the granules are screened and blended with the magnesiumstearate. The granules are then compressed into tablets using 7 mmdiameter punches.

Tablets of other strengths may be prepared by altering the ratio ofactive ingredient to lactose or the compression weight and using punchesto suit.

Example

    ______________________________________                                        ORAL FORMULATION                                                              Capsules:                                                                                  mg/capsule                                                       Formula        A           B      C                                           ______________________________________                                        Active Ingredient                                                                            2.0         4.0    8.0                                         R(+) ondansetron                                                              Starch 1500    97.0        95.0   91.0                                        Magnesium Stearate BP                                                                        1.0         1.0    1.0                                         Compression weight                                                                           100.0       100.0  100.0                                       ______________________________________                                    

The active ingredient is sieved and blended with the excipients. The mixis filled into size No. 2 hard gelatin capsules using suitablemachinery. Other doses may be prepared by altering the fill weight an ifnecessary changing the capsule size to suit.

Example

    ______________________________________                                        INTRAVENOUS FORMULATION                                                       Formula            μg/ml                                                   ______________________________________                                        Active Ingredient  400                                                        R(+) ondansetron                                                              Dilute Hydrochloric Acid BP                                                                      to pH 3.5                                                  Sodium Chloride Injection BP                                                                     1 ml                                                       ______________________________________                                    

What is claimed is:
 1. A pharmaceutical composition suitable foradministration to a mammal which comprises an amount of R(+) ondansetronor a pharmaceutically acceptable salt thereof, substantially free of itsS(-) stereoisomer; and a pharmaceutically acceptable carrier, whereinthe amount is about 2.0 mg to about 8.0 mg.
 2. A composition accordingto claim 1, which comprises R(+) ondansetron hydrochloride.
 3. Acomposition according to claim 2, adapted for oral administration.
 4. Acomposition according to claim 2, adapted for intravenous delivery.
 5. Acomposition according to claim 2, adapted for use in a transdermaldelivery formulation.
 6. A composition according to claim 2, adapted foruse as a transdermal patch.
 7. The pharmaceutical composition of claim1, wherein said mammal is a human.
 8. The pharmaceutical composition ofclaim 3, wherein the orally administered composition is from one tothree unit doses per day.
 9. The pharmaceutical composition of claim 8,wherein the orally administered composition is from one to two unitdoses per day.